mmg_233_2013_genetics_genomicswikiaorg-20200214-history
Origin and evolution of the hippo signaling pathway
Hippo signaling is an evolutionarily conserved pathway that controls organ size by regulating cell proliferation, apoptosis, and stem cell self renewal. Core to the Hippo pathway is a kinase cascade, where Mst1/2 (ortholog of Drosophila Hippo) kinases and Sav1 form a complex to phosphorylate and activate LATS1/2 when it forms a complex with its regulatory protein MOB1. This activation in turn phosphorylates and inhibit the transcription co-activator, YAP, which is a major downstream effector of the Hippo pathway. 2 Two outcomes in this pathway are: When YAP is dephosphorylated, it translocates into the nucleus and interact with TEAD1-4 domain and other transcription factors to induce expression of genes that promote cell proliferation and inhibit apoptosis. When YAP is phosphorylated, it interacts with 14-3-3 protein molecules and stays in the cytoplasm. Evolution of Gene This pathway highly conserved among species. Each species has a different ortholog of the Hippo kinase. In mammals, the two Yki orthologs are Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). 3 Within the pathways, each species has different proteins that have the same fuction in the pathway. Wts is LATSS1/2 in mammals. Mob is also known as Mats. Sav is WW45 in mammals. Mats is MOBKL1A/B in mammals. The transcription coactivator is Yorkie (Yki) or YAP/TAZ in mammals. Yap does not have its own DNA binding domain so it has to bind to other factors first in order to bind to DNA. Merlin is NF2 in mammals. In addition, dysregulation of the Hippo pathway contributes to cancer development. When YAP is dephosphorylated and translocates into the nucleus it induces expression of genes that promote cell proliferation and inhibits apoptosis. When YAP is phosphorylated it stays in the cytoplasm and leads to apoptosis because of the proteasomal degradation and cytoplasmic sequestration. So, this mechanism needs to be regulated because any errors or mutations will lead to cancer if genes that promote proliferation is always turned on. Bioinformatic tools were used to study the evolution of the Hippo/YAP pathway focusing on the transcriptional coactivator YAP, which is a pivotal effector of the pathway. The aim was to establish the origin and mode of development of YAP and its pathway in the animal world. Some pathway members can be already identified in single-celled eukaryotes like the yeast that have preceded multicellular animals. Interestingly, some components found that are present in human are also in the sea-anemone Nematostella, which belongs to a very basal group of metazoans, the cnidarians. All the major domains of YA P have been conserved between cnidarians and mammals, and YAP can be identified even in the more basal placozoan clade. There is also a very high degree of conservation in regions such as the WW and the TEAD-binding domains, TEAD being the major DNA-binding partner of YAP. The evolutionary changes in YAP and in other main components of the pathway begins from the first metazoans such as sponges. YAP and its binding partner TEAD demonstrate strong coevolution. References 1. http://en.wikipedia.org/wiki/Hippo_signaling_pathway#Summary_Table 2. Saucedo, Leslie J.; Edgar, Bruce A. (2007). "Filling out the Hippo pathway". Nature Reviews Molecular Cell Biology 8''' (8): 613–21 3. Wang, Kainan; Degerny, Cindy; Xu, Minghong; Yang, Xiang-Jiao (2009). "YAP, TAZ, and Yorkie: A conserved family of signal-responsive transcriptional coregulators in animal development and human diseaseThis paper is one of a selection of papers published in this Special Issue, entitled CSBMCB's 51st Annual Meeting – Epigenetics and Chromatin Dynamics, and has undergone the Journal's usual peer review process". Biochemistry and Cell Biology '''87 (1): 77–91